ABSTRACT Histone methylation is fundamental to the organization of chromatin and in the regulation of gene transcription. We will continue our long-term goal of elucidating how lysine-specific histone methyltransferases regulate gene expression and contribute to cellular development and disease. Our established model for this goal is determining the functions of the Set2 methyltransferase, which catalyzes H3 lysine 36 methylation (H3K36me). We and others have shown that Set2 functions through an association with elongating RNA polymerase II to recruit a variety of chromatin-modifying activities to genes that maintain a suppressed chromatin state resistant to pervasive transcription and histone exchange. The significance of Set2 to cellular physiology is underscored by the fact that the human homolog of Set2, SETD2, is one of the most frequently mutated proteins in cancer, comparable with p53 and RB. Despite the significance of Set2, we know little about how the deposition and removal of this chromatin mark contributes to cellular biology. This incomplete knowledge about H3K36 methylation function is exemplified by our preliminary findings that reveal not only a role for Set2 in control of the cell cycle, but the existence of a novel H3K36 demethylase that may regulate gene transcription through maintaining promoter demethylation. We hypothesize that the regulation of transcription fidelity by Set2/H3K36me is critical for the precise transcription programs necessary for cell cycle progression. We also hypothesize that Ecm5 is a H3K36-specific demethylase that functions to maintain promoter function of genes targeted by the complex Ecm5 is found in. By determining how Set2/H3K36me functions, we will eliminate significant deficiencies in the understanding of chromatin function.